1)The potential toxicity of gene therapy and/or embryonic stem cell manipulation is being evaluated in a cohort of mice that carry an obesity and hyperlipidemia phenotype. They resulted from experiments that were designed to create a homeobox knockout using embryonic stem cells. An evaluation is being carried out to determine if some portion of the targeting vector used to create the knockout has integrated in the genome disrupting an important gene in weight regulation and hyperlipidemia. Additionally the obese animals that were terminally sacrificed had tumors, while none of the control normal sized heterozygous knock out animals of a similar age had tumors. 2) Adenoviral toxicity has been evaluated with regards to platelets. In clinical studies using adenoviral vectors, thrombocytopenia is observed particularly in patients receiving an intravenous administration. In vitro, no direct effect of adenoviral vectors on inhibiting or stimulating platelet aggregation was observed. Additional in vitro studies, attempting to simulate in vivo conditions will evaluate the potential interactions of adenoviral vectors with endothelial cells,leukocytes and platelets individually as well as combined. In vivo studies non-human primate studies to be done in collaboration with the NIH are also planned to evaluate the contribution of pre-existing immunity to 1)overall toxicity, 2)apparently low levels of transfection efficiency, and 3) to ascertain if the observed thrombocytopenia is due to decreased platelet synthesis, increased destruction or redistribution.